Design, synthesis, and biological activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists
文献类型：期刊论文
| 作者 | Zhang, Denggao7; Gui, Jiangwen5,6; Kong, Linghui7; Hu, Chuyuan3,4,5; Kou, Xinmeng7; Wang, Biying2,5; Duan, Shaoliang7; Liu, Min5; Li, Zixiang7; Luo, Jiawen5,6 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-12-01 |
| 卷号 | 130页码:13 |
| 关键词 | 4,5-Epoxymorphinans DOR-selective agonists Structure-activity relationships |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2025.118373 |
| 通讯作者 | Liu, Jinggen(jgliu@simm.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn) ; Wang, Yujun(yjwang@simm.ac.cn) ; Li, Wei(wei-li@fudan.edu.cn) |
| 英文摘要 | The delta opioid receptor (DOR) is a promising target for developing analgesics with fewer side effects compared to mu opioid receptor (MOR) agonists. However, non-peptidyl DOR-selective agonists remain limited. Using the "message-address" concept in opioid ligand design, we designed and synthesized a series ofpara-substituted N-cyclopropylmethyl-7 alpha-phenyl-6,14-endoetheno-tetrahydronorthebaines to explore their binding affinity and selectivity for DOR over MOR and kappa opioid receptor (KOR). Key findings revealed that para-substituted phenylamino derivatives exhibited high DOR affinity and subtype selectivity. Functional assays confirmed their agonistic activity at DOR, with compounds 4a and 4e showing IC50 values of 580.9 nM and 4807 nM, respectively. Molecular modeling studies revealed that DOR selectivity might be mediated by specific interactions with residue L3007.35 in the TM7 domain, where structural rearrangement of the address component facilitates its transition from KOR-to DOR-selective binding modes. These findings highlight the critical role of "address" component optimization in achieving receptor subtype specificity, providing a structure-based strategy for developing new opioid therapeutics with tailored pharmacological profiles. |
| WOS关键词 | MESSAGE-ADDRESS CONCEPT ; ANTIDEPRESSANT-LIKE ; BIVALENT LIGANDS ; POTENT ; ANTAGONISTS ; RECOGNITION ; DISCOVERY ; ANTINOCICEPTION ; KNT-127 ; ROLES |
| 资助项目 | Key R & D Program of Shandong Province, China[2024CXPT029] ; Major Project of the Science and Technology Innovation 2030 of China[2021ZD0203500] ; Major Project of the Science and Technology Innovation 2030 of China[2021ZD0202900] ; National Natural Science Foundation of China[82030112] ; National Natural Science Foundation of China[82273853] ; National Natural Science Foundation of China[82073765] ; Natural Science Foundation of Shanghai[24ZR1413700] ; Natural Science Foundation of Shanghai[23ZR1474900] ; Fundamental Research Projects of Science & Technology Innovation and development Plan in Yantai City[2024JCYJ045] ; Taishan Scholars Program ; Shandong Laboratory Program[SYS202205] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001566417100001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321429]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liu, Jinggen; Shao, Liming; Wang, Yujun; Li, Wei |
| 作者单位 | 1.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, 548 Binwen Rd, Hangzhou 310053, Peoples R China 2.Yantai Univ, Sch Pharm, 30 Qingquan RD, Yantai 264005, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 5.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, 198 Binhai Rd, Yantai 264117, Shandong, Peoples R China 6.Anhui Univ Chinese Med, Sch Pharm, Hefei 230012, Peoples R China 7.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Denggao,Gui, Jiangwen,Kong, Linghui,et al. Design, synthesis, and biological activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2025,130:13. |
| APA | Zhang, Denggao.,Gui, Jiangwen.,Kong, Linghui.,Hu, Chuyuan.,Kou, Xinmeng.,...&Li, Wei.(2025).Design, synthesis, and biological activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists.BIOORGANIC & MEDICINAL CHEMISTRY,130,13. |
| MLA | Zhang, Denggao,et al."Design, synthesis, and biological activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists".BIOORGANIC & MEDICINAL CHEMISTRY 130(2025):13. |
入库方式： OAI收割
来源：上海药物研究所
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